Circulating hematopoietic stem and progenitor cells are myeloid-biased in cancer patients

Abstract

Cancer is associated with a profound perturbation in myelopoiesis that results in the accumulation of myeloid-derived suppressor cells (MDSCs) to promote disease progression. Recent studies in mice suggest that tumor-derived factors could regulate the differentiation of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow and subsequently contribute to dysregulation of hematopoiesis. However, the nature and role of HPSCs in patients with cancer remain unknown. Here we show, in detailed studies of the peripheral blood from 133 untreated patients with seven different types of tumors, that the composition of circulating HSPCs was significantly altered in patients with solid tumors. The frequencies of circulating granulocyte-monocyte progenitors (GMPs) were increased four to seven fold in all types of tumors examined, and the circulating hematopoietic precursors exhibited myeloid bias with a skew toward granulocytic differentiation in patients with solid tumors. These myeloid precursors are selectively enriched in tumor tissues, and the high levels of circulating GMPs were positively correlated with disease progression. By using cord blood-derived CD34 + cells, we developed an in vitro short-term culture model to effectively induce the rapid generation of MDSCs. We found that, among the factors produced by various tumors, GM-CSF, granulocyte colony-stimulating factor, and IL-6 could not only promote the myeloidbiased differentiation, but also induce the differentiation of myeloid precursors into functional MDSCs. These findings suggest that the altered circulating HSPCs may serve as an important link between dysregulated bone marrow hematopoiesis and accumulated MDSCs in patients with cancer.

Targeting Suppressive Myeloid Cells Potentiates Checkpoint Inhibitors to Control Spontaneous Neuroblastoma

“…However, the detailed mechanisms of this effect in humans remain elusive. In a recent study, Wu and colleagues confirmed the role of GM-CSF and IL6 during the expansion of MDSCs from human CD34 þ hematopoietic progenitor cells (46). Utilizing murine bone marrow cells, human CD34 þ hematopoietic progenitor cells and a human monocyte-neuroblastoma coculture model, we provided insightful results emphasizing the key contribution of the M-CSF/CSF-1R pathway during the induction of MDSCs and TAMs.…”

Adjuvant cellular immunotherapy in patients with resected primary non-small cell lung cancer

“…Meanwhile, immune effector cells not only produce large amounts of inflammatory cytokines to alleviate immune damage caused by anticancer drugs and enhance the immunosurveillance capabilities of patients with cancer, 37 but additionally eliminate potential or residual tumor cells after chemotherapy, including even drug-resistant tumor cells and putative cancer stem cells. [38][39][40] Secondly, alternate application of CIK and NK cells exhibits a synergistic antitumor immunity via different mechanisms compared to the CIT with only CIK cells, which was also found by Maniar et al and Cui et al 34,35 On the other hand, it was reported that the circulating hematopoietic stem and progenitor cells from various patients with solid cancers exhibited a generalized myeloid bias with a skew toward granulocytic differentiation, 41 which increased the neutrophil-to-lymphocyte ratio (NLR), a poor prognostic indicator. 42 Adjuvant CIT could reverse the NLR, resulting in immune equilibrium to reduce tumor recurrence and metastasis.…”

Invasive breast cancer reprograms early myeloid differentiation in the bone marrow to generate immunosuppressive neutrophils

“…Expansion of these early BM compartments by G-CSF could provide a constant supply of lineage-committed progenitors during tumor-induced production of Ly6G + neutrophils. This would also explain the increased number of granulocytemacrophage colony-forming units observed in BM of HER2 transgenic BALB/c tumor-bearing mice (49), and the increased numbers of circulating HSPCs observed in the blood of human patients with different types of carcinomas that also show elevated G-CSF levels (50). The pleiotropic mechanisms by which G-CSF regulates myeloid progenitor differentiation and proliferation (51), apoptosis of mature neutrophils (52), and priming of neutrophil activation (53), together with our previously unidentified observations of expansion of HSCs and MPPs, support the hypothesis that pathways involved in immune activation are also linked to early hematopoiesis to fulfill the demand of the immune system (35).…”

“…Skewing of HSPC differentiation toward the myeloid lineage has been reported in mouse models (30,49) and in human patients (50) with different types of solid tumors, but until now the mechanism responsible was not known. Our data demonstrate a previously unidentified mechanism for the production of T cell-suppressive neutrophils in which early compartments of the hematopoietic hierarchy in BM are regulated by tumor-derived G-CSF.…”